This invention relates to a new and improved method for inducing or pacing atrial and ventricular arrhythmias in animals. The methods and compositions of the invention can be used to pace patients, convert patients out of atrial fibrillation, convert patients with ventricular rhythm disturbances and even as a diagnostic to assess a patients risk for arrhythmias.
Normal sinus rhythm of the heart begins with the sinoatrial node (or xe2x80x98SA nodexe2x80x99) generating a depolarization wave front. The impulse causes adjacent myocardial tissue cells in the atria to depolarize, which in turn causes adjacent myocardial tissue cells to depolarize. The depolarization propagates across the atria, causing the atria to contract and empty blood from the atria into the ventricles. The impulse is next delivered via the atrioventricular note (or xe2x80x98AV nodexe2x80x99) and the bundle of HIS (or xe2x80x98HIS bundlexe2x80x99) to myocardial tissue cells of the ventricles. The depolarization of these cells propagates across the ventricles, causing the ventricles to contract.
This conduction system results in the organized sequence of myocardial contraction leading to a normal heartbeat.
Sometimes aberrant conductive pathways develop in heart tissue, which disrupt the normal path of depolarization events. For example, anatomical obstacles in the atria or ventricles can disrupt the normal propagation of electrical impulses. These anatomical obstacles (called xe2x80x98conduction blocksxe2x80x99) can cause the electrical impulse to degenerate into several circular wavelets that circulate about the obstacles. These wavelets, called xe2x80x98reentry circuits,xe2x80x99 disrupt the normal activation of the atria or ventricles. As a further example, localized regions of ischemic myocardial tissue may propagate depolarization events slower than normal myocardial tissue. The ischemic region, also called a xe2x80x98slow conduction zone,xe2x80x99 creates errant, circular propagation patterns, called xe2x80x98circus motion.xe2x80x99 The circus motion also disrupts the normal depolarization patterns, thereby disrupting the normal contraction of heart tissue.
The aberrant conductive pathways create abnormal, irregular, and sometimes life-threatening heart rhythms, called arrhythmias. An arrhythmia can take place in the atria, for example, as in atrial tachycardia or atrial flutter. The arrhythmia can also take place in the ventricle, for example, as in ventricular tachycardia.
Atrial fibrillation is one of the most common arrhythmias, and is usually associated with patients of an increased age. About ten percent of patients who are at least 65 years old present with atrial fibrillation. Atrial fibrillation is associated with troublesome symptoms for patients, and also has a significantly adverse influence on the cardiac function. It is also well known that there is an increased risk of embolic events following atrial fibrillation. Accordingly, the increased heart rate associated with atrial fibrillation needs to be controlled. The primary current treatments for atrial fibrillation as the use of anti-arrhythmic drugs, or electric cardioversion. Use of anti-arrhythmic drugs is often associated with potential proarrhythmic effects, especially in patients with already compromised ventricular function. Such a proarrhythmic effect can outweigh the potential benefit of drug administration. On the other hand, transthoracal electrical cardioversion is an extreme therapy, requiring a discharge energy in the range of 50 to 360 Joules. This treatment requires general anesthesia, and serious side effects may occur as a result. Often patients receive superficial skin burns at the site of the shock. Additionally distressing is the fact that there are a substantial number of patients who may not be cardioverted externally, requiring invasive transvenous cardioversion.
As can be seen, a need exists in the art for a method of inducing or pacing atrial or ventricular rhythms which is noninvasive, safe and nontoxic to patients.
It is an object of the present invention to provide a safe nontoxic microbubble composition and method which can be used to induce cardiac rhythms in animals.
It is yet another object to provide a method of inducing or pacing cardiac rhythms which is noninvasive and does not require anesthetic.
These and other objects of the invention will become apparent from the description of the invention which follows.
According to the invention a cardiac rhythm therapy is provided which is noninvasive, painless and non toxic. The therapy involves the combination of low frequency transthoracic ultrasound and a pharmaceutical composition. The composition comprises microbubbles of a diameter of about 0.1 to 10 microns, the interior of which has been enhanced with an insoluble gas such as fluorocarbon gas, helium or sulfur hexafluoride and which gas is encapsulated in a protein-coated shell. The invention uses agents and methods traditionally used in ultrasound imaging and as such provides a means for visualization of the heart as the rhythm is induced. Quite unexpectedly it was found that the insoluble gas microbubbles of the invention in combination with low frequency ultrasound act themselves inducing, or pacing atrial and ventricular rhythms in animals, and induction can be manipulated by directing the ultrasound to either the atrium or ventricle. This strategy can be used in any of a number of cardiac rhythm strategies. For example it can be used to non-invasively convert patients to a regular rhythm from atrial fibrillation. It could also be used as a diagnostic to identify patients who are vulnerable to ventricular rhythm disturbances. These are just two examples of potential uses for this strategy and are not intended to limit the invention in any way. Other uses are described and exemplified herein and will be obvious to those of skill in the art from the teachings herein.